The firing of neurons in specific temporal and spatial patterns underlies all the major functions of the nervous system. External stimuli are detected by the excitation of specific sensory neurons, enabling vision, hearing, touch, taste, and smell. Neuronal excitation also enables humans and other animals to move and interact with their environments. Therefore, methods for controlling neuronal excitation could be used to regulate sensation and motor control and to correct nervous system disorders including pain, inflammation, Parkinson's disease, neuron damage, epilepsy, depression, and others. In the clinic, manipulating neuronal activity has required the use of drugs which offer poor spatial and temporal control, and electrical stimulation, which requires placement of electrodes with attendant tissue damage and distortion (Henderson J M, et al., Neurosurgery. 2009 64:796-804).
Electromagnetic radiation (e.g. light) is a stimulus that can be controlled with high temporal and spatial resolution. If neuronal activity could be modulated by electromagnetic radiation, it would offer a powerful means of manipulating the nervous system for research and therapy. Indeed, one of the most influential recent innovations in neuroscience has been optogenetics, an approach in which neurons are rendered photosensitive by causing them to express electromagnetic radiation-activated bacterial opsins such as channelrhodopsin or halorhodopsin (Boyden E S, et al., Nat Neurosci. 2005 8:1263-8; Zemelman B V, et al., Neuron. 2002 33:15-22; Miesenbock G. Science. 2009 326:395-9). Optogenetics has yielded remarkable new insights in cultured cells and in some model organisms, but its use is limited to systems that can be manipulated by transgenesis to express the bacterial opsins. Therefore, current optogenetic approaches are not applicable in the clinic as they do not provide a means to control endogenous neuronal proteins and neuronal signaling in non-transgenic animals with electromagnetic radiation.
Some optogenetics work has been performed with photorelease of caged glutamate, which provides optical control of glutamate receptors in brain slices. Azobenzene-containing photoswitchable ligands have also been designed to control glutamate receptors and potassium channels6,7,16-23. However, virtually all prior work in chemical optogenetics has been limited to cultured cells, tissue slices, and other ex vivo preparations because most existing techniques are not effective in vivo.
TRP channels are involved in diverse sensory systems including vision, taste, temperature and touch. TRPA1 signaling contributes to illnesses including neuropathic pain and chronic inflammation25-28. Precise control of TRPA1 channels may be useful for understanding and treating these disorders. However, currently available TRPA1 ligands like mustard oil and cinnamaldehyde provide imprecise spatiotemporal control of TRPA1 signaling.